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Review
Aging: An important factor for the pathogenesis of neurodegenerative diseases
Tahira Farooqui a,*, Akhlaq A. Farooqui b
a Department of Entomology, The Ohio State University, 318 West 12th Avenue, Columbus, OH 43210, USAb Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, USA
1. Introduction
Aging is a time-dependent progressive functional impairment
process thatleads to mortality. The most prominent characteristics
of aging are a progressive decrease in physiological capacity, a
reduced ability to respond adaptively to environmental stimuli, an
increased susceptibility to diseases, and increased mortality. Many
theories have been advanced to explain aging, but the biological
mechanism(s) that underlie aging are still unknown. Major
hypotheses of aging include altered proteins (Levine and Stadtman,
1996); DNA damage and less efficient DNA repair (Harley, 1991);
inappropriate cross-linking of proteins, DNA, and other structural
molecules (Bjorksten, 1974); a failure of neuroendocrine secretion
(Mobbs, 1996); cellular senescence in the cell culture system
(Hayflick, 1965); an increase in free radical-mediated oxidativestress(Harman, 1981); andchangesin the order of gene expression
(Helfand and Rogina, 2000).
A widely accepted concept is that the pattern of ontogenic
development within each species is genetically determined
(Robert and Labat-Robert, 2003). Therefore, a possible cause of
aging may be genetic: a gradual deterioration in molecular
components (e.g., loss of code, loss of gene expression devices,
loss of conditions for gene expression, improper gene regulation), a
concerted functioning of which is vital for cell viability and
proliferation (Robert and Labat-Robert, 2003). Several classes of
genes that differentially express during aging have been identified
in monkeys using high-density oligonucleotide microarrays in the
corpus callosum (Duce et al., 2008). These genes predominantly
modulate an increase in stress factors and a decrease in cell
function. The cell function changes include increased cell cycle
inhibition and proteolysis, as well as a decrease in mitochondrial
function, signal transduction, and protein translation. While most
of these categories have previously been reported in functional
brain aging(Guttmann et al., 1998), this was the first timethey had
been associated directly with white matter. Microarray analysis
has also enabled the identification of age-activated neuroprotec-
tive response pathways in white matter, as well as several genesimplicated in lifespan. Of particular interest was the identification
of Klotho, a multifunctional protein that regulates phosphate and
calcium metabolism, as well as insulin resistance, and is known to
defend against oxidative stress and apoptosis (Duce et al., 2008).
Other factors that control aging are a decrease in the efficacy of
DNA repair (Barnett and King, 1995), telomere-associated end-
replication problems (Allsopp et al., 1995), and mitochondrial DNA
mutations (Ozawa, 1995). A decline in these components may also
be related to cellular senescence, apoptosis, and aging-associated
pathologies. While no single theory accounts for all aspects of
aging, recent studies suggest that the primary aging process is
Mechanisms of Ageing and Development 130 (2009) 203215
A R T I C L E I N F O
Article history:
Received 1 May 2008
Received in revised form 1 October 2008
Accepted 12 November 2008Available online 21 November 2008
Keywords:
Aging
Alzheimer disease
Parkinson disease
ROS-mediated damage
Neurodegenerative diseases
Anti-aging remedies
A B S T R A C T
Aging is a natural process that is defined as a progressive deterioration of biological functions after the
organism has attained its maximal reproductive competence. Aging leads to the accumulation of
disabilities and diseases that limit normal body functions and is a major risk factor for
neurodegenerative diseases. Many neurodegenerative diseases share oxidative stress and nitrosative
stress as common terminal processes. According to free radical theory of aging, an elevation in reactive
oxygen species (ROS) and reactive nitrogen species (RNS) damages neural membranes and induces
oxidative and nitrosative stress. The increase in oxidative and nitrosative stress is accompanied by the
concomitant decline in cognitive and motor performance in the elderly population, even in the absence
of neurodegenerative diseases. Markedly increased rates of oxidative and nitrosative stress are themajor
factors associated with the pathogenesis of neurodegenerative diseases. Diet is a key environmental
factor that affects the incidence of chronic neurodegenerative diseases. Dietary supplementation with
polyphenols, resveratrol, ginkgo biloba, curcumin, ferulic acid, carotenoids, flavonoids, and n-3 fatty
acids exerts beneficial effects not only through the scavenging of free radicals, but also by modulating
signal transduction, gene expression, and restoring optimal neuronal communication.
2008 Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: +1 614 783 4369.
E-mail address: farooqui.2@osu.edu (T. Farooqui).
Contents lists available at ScienceDirect
Mechanisms of Ageing and Development
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m e c h a g e d e v
0047-6374/$ see front matter 2008 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.mad.2008.11.006
mailto:farooqui.2@osu.eduhttp://www.sciencedirect.com/science/journal/00476374http://dx.doi.org/10.1016/j.mad.2008.11.006http://dx.doi.org/10.1016/j.mad.2008.11.006http://www.sciencedirect.com/science/journal/00476374mailto:farooqui.2@osu.edu8/14/2019 antiageing supplements
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under genetic control with contributions from environmental
factors, supporting a link between oxidative stress and life span
(Martin and Grotewiel, 2006).
2. Aging, diseases, and learning
Aging produces several changes in human brain. The human
brain shrinks with aging. It is presumed that decrease in weight
and volume in the aging brain occur due to a loss of neurons and
myelinated axons (Peters, 2002). Changesin brain whitematter are
prominent features of the aging brain. These changes are
accompanied by the overexpression and calpain-mediated pro-
teolytic fragmentation of 20,30-cyclic nucleotide 30-phosphodies-
terase, resulting in myelin and axonal pathology in the aging brain
(Hinman et al., 2008). An increase in microglial activation also
occurs in several brain regions, including the hippocampus, during
aging (Finch and Cohen, 1997). Possible mechanisms may include
microglial reaction to advanced glycation end products (AGEPs)
(Morgan et al., 1999), which activate nuclear transcription factor-
kappaB (NFkB) and induce the transcription of pro-inflammatory
cytokines during aging (May and Ghosh, 1998). Thus, age-
dependent alterations in gene expression cause a disruption of
metabolic homeostasis (Mattson, 2002; Mocchegiani et al., 2006).
Learning is one of the memory processes through which thebrain adapts in response to environmental input. Memory is
defined as the persistence of learning over time through the
storage and retrieval of information and accounts for all knowledge
gained through experience. Memory includes: (1) learning or
encoding, (2) short-term or long-term storage and (3) recall or
retrieval. Therefore, if we test recall, it will tell us what we learned.
We cannot considerlearningwithout memory, or memory without
learning (Agranoff et al., 1999). There are several forms of memory.
One form of memoryis the ability to consciously and directly recall
or recognize recently processed information, where impairment of
this form of memory is a defining feature of global amnesia. It is
well known that, with increasing age, recall andrecognition of new
facts and events decline. The decline in memory performance is
closely related to age-mediated structural and functional changesin the hippocampus (Rosenzweig and Barnes, 2003). Memory is
also affected by age-related changes in the prefrontal cortex and
frontal white matter tracts, which may lead to impaired
interactions between the prefrontal cortex and hippocampal
structures. In the elderly, memory loss occurs as a natural result
of aging. A decline in brain performance, including learning and
memory, in the elderly is due to a deterioration of synaptic contact
and changes in the levels of neurotransmitters and neurohormones
(Nieto-Sampedro and Nieto-Diaz, 2005). Since the elderly popula-
tion is growing, there is a need to synthesize new drugs with
memory-enhancing properties. Neurodegenerative diseases can
affect some forms of memory while leaving others relatively intact
(Pennanen et al., 2006; Hudson, 2008; Ohsawa et al., 2008).
3. Oxidative stress, aging, and neurodegenerative diseases
Oxidative stress refers to cytotoxic consequences caused by
oxygen free radicals generated in a cell by processes that utilize
molecular oxygen. Oxidative damage is inflicted by ROS, impli-
cated in the cause of certain diseases, and has an impact on the
bodys aging process. ROS is a collective term that includes oxygen
radicals and non-radical oxidizing agents that can be converted
into radicals. At low levels, ROS function as signalingintermediates
for the modulation of fundamental cell activities such as growth
and adaptation responses, but at higher concentrations, ROScontribute to neuronal membrane damage. Almost every gene that
has been implicated in the response to stress has been shown to be
affected by altered ROS levels (Allen and Tresini, 2000). Mitochon-
dria are the major producer of ROS (Fig. 1). Another source of ROS
generation is polyunsaturated fatty acids, which are components
of neural membrane glycerophospholipids. These glyceropho-
spholipids are enriched in arachidonic acid (AA) (20:4 n-6) and
docosahexaenoic acid (DHA) (22:6 n-3). Enzymic and non-enzymic
oxidation of these fatty acids generates ROS. Interactions of these
fatty acids with the trace metal ion Fe3+ results in membrane lipid
peroxidation and an intensification of ROS formation. In addition,
ROS are produced by NADPH oxidase 4 (Nox 4). NADPH oxidase in
astrocytes and microglial cells is regarded as a major sourceof ROS
for mediating oxidative stress and neuroinflammation (Qin et al.,2002; Zekry et al., 2003).
Fig. 1. Generation of reactive oxygenspecies (ROS) innormal agingand neurodegenerative diseases.Generationof lowlevelsof ROSduring normalagingis counteredby anti-
oxidant enzymes. Generation of high levels of ROS and downregulation of anti-oxidant mechanisms results in neural cell death in neurodegenerative diseases.
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ROS formation causes oxidative damage to membranes,
proteins, lipids and genes, where this can be controlled by the
bodys defense mechanisms. ROS-mediated oxidative damage has
been implicated in normal aging and various neurodegenerative
diseases (Selley et al., 2002; Zarkovic, 2003; Kikuchi et al., 2002;
Giuliano et al., 2003; Hartzler et al., 2002). Thus, levels of lipidperoxides, such as 4-hydroxynonenal (4-HNE) and 8-hydroxy-20-
deoxyguanosine, are markedly increased in neurodegenerative
diseases. 4-HNE reacts with nucleophiles to form Michael adducts
and Schiff bases, resulting in the modification of many enzymes
and cytoskeletal proteins (Musiek et al., 2005; Farooqui and
Horrocks, 2006).
During aging, astrocytes generate a large amount of nitric oxide
(NO), which may be deleterious to the neighboring neurons and
oligodendrocytes. The exact molecular mechanisminvolved in NO-
mediated neuronal damage is not known. However, the reaction
between NO and superoxide generates peroxynitrite (ONOO)
(Fig. 2), which not only interacts with sulfhydryl groups, but can
hydroxylate the aromatic rings of amino acid residues (Beckman
et al., 1992). S-nitrosylation of cysteine thiols contributes to NO-mediated neurotoxicity by triggering the misfolding of proteins, a
process that may contribute to the pathogenesis of neurodegen-
erative diseases in old age (Nakamura and Lipton, 2008).
Furthermore, the generation of NO leads to S-nitrosylation of
wild-type parkin and initially to a marked increase, followed by a
decrease, in the activity of E3 ligase-ubiquitin-proteasome
degradative pathway (Yao et al., 2004). The inhibition of parkins
ubiquitin E3 ligase activity by S-nitrosylation could contribute to
the degenerative process in neurodegenerative disorders by
impairing the ubiquitination of parkin substrates. In addition,
ONOO reduces mitochondrial respiration, inhibits membrane
pumps, depletes cellular glutathione, and damages DNA, thus
activating poly-(ADP-ribose) synthase, an enzyme that leads to
cellular energy depletion(Pryor and Squadrito, 1995) (Fig.2). Thus,
ONOO reacts with lipid, proteins, and DNA (Radi et al., 1991). It is
also reported that ONOO interferes with key enzymes of the
tricarboxylic acid cycle, the mitochondrial respiratory chain, and
mitochondrial Ca2+ metabolism (Bolanos et al., 1997). All these
processes may contribute to a deficiency of neuronal energy and
the oxidation of protein sulfhydryls caused by aging-associatedchanges as well as neurotraumatic situations (Thomas and Mallis,
2001).
Brain tissue contains specific enzymes to deal with ROS in the
cytoplasm, as well as in neural membranes, where catalase,
superoxide dismutase and glutathione peroxidase detoxify ROS.
Superoxide dismutase converts the superoxide anion radical
into hydrogen peroxide, which can readily diffuse through
neural membranes (Calabrese et al., 2004). Hydrogen peroxide
itself is not a free radical, but a major source for the generation
of hydroxyl radical that is formed in the Fenton reaction
catalyzed by iron and copper. Hydrogen peroxide is removed by
glutathione peroxidase and catalase. Collectively, these studies
suggest that oxidation of glycerophospholipids, chemical cross-
linking of neural membrane proteins and oxidation of neuralcell DNA are significant chemical events that are associated
with oxidative stress and the disruption of ion homeostasis
during lipid peroxidation. All these processes are related to
oxidative stress-mediated neurodegeneration in neurodegen-
erative diseases.
Interaction with iron ions perturbs the structure of glyceropho-
spholipid bilayers, producing changes in membrane fluidity and
affecting function. Several biomarkers of oxidative stress in
Alzheimers disease (AD) and Parkinsons disease (PD) have been
identified (Farooqui and Horrocks, 2007; Beal, 2004). The
accumulation of iron in these disorders occurs not only at the
sites of specific neurodegeneration, but also in other brain regions,
indicating that the accumulation of iron may be a secondary
process associated with neurodegeneration.
Fig. 2. Production of ROS and RNS and synthesis of peroxynitrite through interactions of nitric oxide and superoxide radical in neural and non-neural cells during aging.
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To manage andsurvivethe effects of aging and differenttypes ofinjuries, brain cells have evolved integrated responses. These are
called longevity assurance processes. These processes involve
several genes (vitagenes) that include members of the HSP system,
such as HSP70 and HSP32, which detect and control diverse forms
of stress. In particular, HSP32, also known as heme oxygenase-1
(HO-1), has received considerable attention, as it has been recently
shown that HO-1 induction, by generating the vasoactive molecule
carbon monoxide and the potent anti-oxidant bilirubin, may
represent a protective system potentially active against oxidative
stress-mediated brain injury (Calabrese et al., 2004). It is proposed
that the maintenance of vitagene activity may possibly delay the
aging process and decrease the occurrence of age-related diseases,
resulting in the prolongation of a healthy life span (Calabrese et al.,
2004).
4. Glycerophospholipids, neurodegenerative diseases, and cell
death
Glycerophospholipids form the backbone of neural membranes.
Aging produces changes in glycerophospholipid-fatty acid com-
position. Arachidonic and docosahexaenoic acids are important
components of neural membranes. A decrease in arachidonic and
docosahexaenoic acids may be related to the activities of
phospholipases A2, C, and D, and enzymic and non-enzymic
oxidation of these fatty acids (Gaiti et al., 1986; Giusto et al., 2002;
Farooqui and Horrocks, 2007). The enzymic oxidation of arachi-
donic acid through cyclooxygenases and lipoxygenases results in
the generation of prostaglandins, leukotrienes, thromboxanes, and
lipoxins. Collectively, these metabolites are called as eicosanoids(Fig. 3). They act through EP1, EP2 and thromboxane receptors
(Phillis et al., 2006). Lipoxins (Fig. 4), generated through the
lipoxygenase pathway, are involved in the resolution of inflam-
mation (Farooqui and Horrocks, 2007). They act through a lipoxin
receptor (ALX), and are involved in the regulation of calcium
mobilization and leukocyte trafficking (Chiang et al., 2006).
The non-enzymic oxidation of arachidonic acid also results in
the generation of isoprostanes (IsoPs) and 4-HNE (Fig. 4) (Farooqui
and Horrocks, 2007). IsoPs are prostaglandin-like mediators
formed non-enzymically by free radical-catalyzed peroxidation
of esterified arachidonic acid in vivo (Greco and Minghetti, 2004).
Non-enzymic oxidation of arachidonic acid also produces isoketals
(Morrow, 2006). Collective evidence suggests that IsoPs and
isoketal are in vivo markers of oxidative stress. In plasma, free andtotal (free plus esterified) F2-isoPs increase with age. In addition,
levels of esterified F2-isoPs increase 68% with age in the liver, and
76% with age in the kidneys. These age-related increases in
esterified F2-isoPs levels correlate well with DNA oxidation, as
measured by 8-oxodeoxyguanosine production, demonstrating
that F2-isoPs are an excellent biomarker for age-related changes in
oxidative damage to membranes (Roberts and Reckelhoff, 2001;
Ward et al., 2005).
In contrast, docosahexaenoic acid is not a substrate for
cyclooxygenases. The action of a 15-lipoxygenase-like enzyme
on docosahexaenoic acid produces 17S-resolvins, 10-17S-docosa-
trienes, and protectins (Hong et al., 2003; Marcheselli et al., 2003;
Serhan and Savill, 2005) (Fig. 4). These second messengers are
collectively known as docosanoids, act through resolvin D
Fig. 3. Interactions between enzymic and non-enzymic lipid mediators of arachidonic acid and docosahexaenoic acid metabolism in the brain. Glutamate receptor, R1 is
coupled to phosphatidylcholine (PtdCho) catabolism, R2 is coupled to plasmalogen (PlsEtn) degradation, R3 is prostaglandin receptors (EP receptors), and R4 is resolvin D
receptors (resoDR1), resolvin E receptors (resoER1), neuroprotectin D receptors (NPDR). Docosanoids not only inhibit the generation of eicosanoids but also modulate signal
transduction through resoDR1, resoER1, and NPDR. Arachidonic acid (AA); docosahexaenoic acid (DHA); 4-hydroxynonenal (4-HNE); and 4-hydroxyhexenal (4-HHE).
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receptors (resoDR1), resolvin E receptors (resoER1), and neuro-
protectin D receptors (NPDR), and are potent endogenous anti-
inflammatory and pro-resolving chemical lipid mediators (Serhan
et al., 2006). They not only antagonize the effects of eicosanoids
and modulate leukocyte trafficking, but also downregulate the
expression of cytokines in glial cells (Hong et al., 2003; Marcheselli
et al., 2003). DHA also undergoes non-enzymic oxidation and
generates neuroprostanes (NP) (Roberts andFessel, 2004; Yinet al.,
2005; Greco and Minghetti, 2004) (Fig. 4). Levels of F4-neuro-
prostanes have been determined in 4-, 10-, 50-, and 100-week-old
male Fischer 344 rats. Levels of F4-neuroprostanes were approxi-
mately 20-fold higher than those of F2-isoprostanes in all age
groups, despite the fact that the brain levels of docosahexaenoic
acid are only twice as high as those of arachidonic acid (Youssefet al., 2003).
Non-enzymic oxidation of DHA also produces neuroketals
(NKs) (Fig. 5) (Bernoud-Hubac et al., 2001). Like IsoK, NKs are very
reactive. They not only form lactam and Schiff base adducts, but
also generate lysine adducts, suggesting that these metabolites
may be involved in proteinprotein cross-linking in brain tissue
under oxidative stress. These metabolites are in vivo markers and
may have neurochemical effects that intensify both neuroinflam-
mation and oxidative stress in acute neural trauma and
neurodegenerative diseases (Roberts and Fessel, 2004; Farooqui
and Horrocks, 2006, 2007).
Although each neurodegenerativedisease has a separate etiology
with distinct morphological and pathophysiological characteristics,
they share oxidative stress as a common mechanism (Farooqui and
Horrocks, 1994). It remainscontroversialwhether oxidative stress is
the cause or consequence of neurodegeneration (Andersen, 2004;
Juranek and Bezek, 2005). Very little information is available on the
rate of neurodegeneration and clinical expression of neurodegen-
erative diseases with age.
ROS also attack proteins and nucleic acids. ROS cross-link
intracellularproteinsandgenerate ceroidpigment,age pigment, and
lipofuscin that accumulates in postmitotic tissues. There is a good
correlation between the accumulation of oxidized/cross-linked
proteins and the decline in proteasome activity and overall cellular
protein turnover during in vitro senescence. These events may
predict a causal relationship during actual cellular aging (Sitte et al.,
2000). Age-mediated ROS generation involves an increase in the
oxidationofDNAandRNAinthecerebellumofmalerats( Cuietal.,inpress). The oxidation of DNA results not only in the generationof 8-
hydroxy deoxy guanosine, but also in DNA protein cross-links in
discrete brain regions of young and aged rats. This age-related
damagein thecortex,striatum, andhippocampuscan be reversed by
glutathione monoester (Murali and Panneerselvam, 2007).
The onset and progression of neurodegenerative diseases may
not only depend upon genetic factors and oxidative stress, but also
on complex interactions between individual genetic background
and environmental factors. The exact role of the risk factors
involved,and theirinfluence on the onset and pacingof thedisease,
is not yet fully understood. Similarly, the relationship between the
rate of neuronal death and the clinical expression of a disease is a
matter for discussion, and more studies of these important topics
are required.
Fig. 4. Chemical structures of enzymic and non-enzymic oxidation products of arachidonicand docosahexaenoic acids. 12-F2t-isoprostane (a); isofuran (b); lipoxin A4 (c); 4-
HNE (d); 16,17-docosatriene (e); 4S5,17S-resolvin (f); 7,16,17S-resolvin (g); and neuroprostane (h).
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Neurodegenerative diseases are marked by site-specific pre-
mature and slow death of certain neuronal populations (Wijsman
et al., 2005; Mizuta et al., 2006; Seonget al., 2005; Pickering-Brown
et al., 2004; Alexander et al., 2002) (Table 1). For example, in AD,
neuronal degeneration occurs in the nucleus basalis, whereas, in
PD, neurons die in the substantia nigra. The most severely affectedneurons in Huntington disease (HD) are striatal medium spiny
neurons. The affected populations of neurons are often, but not
always, synaptically interconnected. The mechanisms associated
with the specificity of neuronal cell death in the nucleus basalis in
AD, the substantia nigra in PD, and the striatum in HD are not
known. However, it is becoming increasingly evident that many
factors including alterations in the energy status of degenerating
neurons, defects in the ubiquitin-proteasome system, the presence
of abnormal aggregated proteins (b-amyloid and tau proteins inAD, a-synuclein and parkin in PD, prion protein in Creutzfeldt-
Jakobs disease (CJD), and huntingtin in HD), a lack of trophic
factors, alterations in the levels of cytokines, along with the
disruption of the ionic gradient and the signal transduction
processes, may contribute to the specificity of neurodegenerative
processes (Farooqui and Horrocks, 2007; Farooqui et al., 2008a).
The most important risk factors for neurodegenerative diseases
are old age and a positive family history. The onset of
neurodegenerative diseases is often subtle, usually occurs in
mid to late life, and their progression depends not only on geneticbut also on environmental factors. Mitochondrial dysfunction and
oxidative stress in neurodegenerative diseases lead to progressive
cognitive and motor disabilities with devastating consequences to
the patients (Farooqui and Horrocks, 2007; Farooqui et al., 2008a).
5. Diagnosis of neurodegenerative diseases
Lipidomics and proteomics have emerged as important
technologies (German et al., 2007; Watson, 2006; Bowers-Gentry
et al., 2006) for the identificationand full characterization ofin vivo
markers for oxidative stress (F2-isoprostane, prostaglandins,
leukotrienes, lipoxins, hydroxyeicosatetraenoic acids, nitrotyro-
sine, carbonyls in proteins, oxidized DNA bases and 4-HNE in the
Fig. 5. Effects of caloric restriction on the brain during aging.
Table 1
Onset, genes, and sites of neuronal loss in familial neurodegenerative diseases.
Neurodegenerative diseases Onset (age) Mutation in genes Site of neuronal loss Reference
AD 3065 PS1, PS2 Nucleus basalis Wijsman et al. (2005)
PD 4060 a-Synuclein,
ubiquitin-protein
ligase (parkin)
Substantia nigra and striatum Mizuta et al. (2006)
HD 2050 Huntingtin Striatum Seong et al. (2005)
P Dis 4060 Tau Frontal and temporal lobes Pickering-Brown et al. (2004)
MSA 52.555 a-Synu clein Sub st an tia nigr a and st riatu m Mizuta et al. (2006)
ALS 4060 SOD1 Upper (brain) and lower (spinal cord) muscles Alexander et al. (2002)
Presenilin1 (PS1), presenilin2 (PS2), amyloid precursor protein (APP), apolipoprotein E (APOE), Huntington gene (HD), superoxide dismutase mutation (SOD1), Picks Disease
(P Dis), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), reactive oxygen species (ROS), multiple system atrophy (MSA), amyotrophic lateral sclerosis
(ALS).
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cerebrospinal fluid (CSF)) (Serhan, 2005; Serhan et al., 2006;
Adibhatla et al., 2006; Milne et al., 2006; Hunt and Postle, 2006;
Morrow, 2006; Lu et al., 2006; Perluigi et al., 2005). The
establishment of automatic systems, including databases, and
accurate analysis of various lipid mediators derived from enzymic
and non-enzymic metabolism of neuronal membrane polyunsa-
turated fatty acids and their metabolites (eicosanoids, resolvins,
neuroprotectins, isoprostanes, neuroprostanes, and isofurans), has
facilitated the identification of key biomarkers associated with
neurodegenerative diseases (Lu et al., 2006).
New mass spectrometry technologies have recently emerged as
important procedures for performing direct tissue analysis using
matrix-assisted laser desorption/ionization (MALDI) sources. This
technique takes mass spectral snapshots of intact tissue slices and
reveals how proteins and peptides are spatially distributed within
a given sample. A major advantage of direct MALDI analysis is the
ability to avoid time-consuming extraction, purification or
separation steps, which may have potential for errors and the
introduction of artifacts (Wisztorski et al., 2007). Direct MALDI
analysis is performed on tissue sections. It allows for the
acquisition of cellular expression profiles while maintaining the
cellular and molecular integrity. With automation and the ability
to reconstruct complex spectral data using imaging software, it is
now possible to produce multiplex imaging maps of selected bio-molecules within tissue sections (Wisztorski et al., 2007). Thus,
direct MALDI spectral data obtained from tissue sections can be
converted into imaging maps, a method now known as MALDI-
imaging. MALDI-imaging combines the power of mass spectro-
metry, namely exquisite sensitivity and unequivocal structural
information, within an intact and unaltered morphological
context. One of the most important developments in recent years
has been the ability to carry out either direct MALDI analysis or
MALDI-imaging on paraffin tissue sections. This capability
provides new avenues for biomarker hunting and diagnostic
follow-up in the clinical setting (Wisztorski et al., 2007).
Furthermore, MALDI-imaging may provide information on the
validation of disease-marker-gene RNA transcripts, which can be
analyzed along with their translational products by targeting theirspecific protein or metabolites. Neurodegenerative diseases, as
well as normal health states, can thus be closely monitored, with a
single technique, at the level of proteins and nucleic acids.
Similarly, single photon emission computed tomography (SPECT),
positron emission tomography (PET), and magnetic resonance
imaging (MRI) are highly sensitive techniques for the early
diagnosis of neuronal cell death in neurodegenerative diseases
and functional changes in the basal ganglia (Gratz et al., 2008).
These have all recently begun to be applied to the diagnosis of
neurodegenerative diseases (Hahn et al., 2008). It may be possible
to use these techniques for the early and reliable diagnosis of
neurodegenerative diseases. SPECT, PET, and MRI scans have
demonstrated diagnostic and prognostic utility for clinicians
evaluating patients with cognitive impairment, and in distinguish-ing among primary neurodegenerative disorders and other
etiologies that contribute to cognitive decline. In addition to
focusing on the cerebral metabolism effects examined with (18)F-
fluorodeoxyglucose, SPECT, PET, and MRI scans can provide
information about other changes that occur in the brains of
patients with neurodegenerative diseases, and cognitively
impaired patients assessable with other radiotracers (Sixverman
et al., 2008). These techniques can also be used to monitor
therapeutic responses in patients with neurodegenerative dis-
eases.
Despite the recent advances in the imaging techniques, the
diagnosis of neurodegenerative diseases is still made by accurate
history and examination (Farooqui and Horrocks, 2007; Farooqui
et al., 2008a,b). Diagnostic accuracy in epidemiological studies
depends on the careful and correct use of clinical diagnostic
criteria. Identificationof molecular biomarkers associated with the
progression of neurodegenerative diseases is necessary for their
detection. Cerebrospinal fluid is important for the detection of
neurodegenerative diseases. Especially early in the course of the
disease, when a correct diagnosis is most difficult, biomarkers like
4-HNE, isoprostanes, isoketal, 8-hydroxy guanosine, b-amyloid,tau protein, and a-synuclein may be quite valuable.
In AD, reduced CSF levels of the Ab42, and increased levels oftotal tau (T-tau) have been detected in numerous studies with a
high degree of sensitivity. However, the specificity of this test in
the diagnosis of other dementiasis lower.The addition of phospho-
tau(P-tau)seems to increase the specificity, since normal levels are
found in other dementias and in cerebrovascular disease
(Andreasen et al., 2003). Increased levels of a-synuclein havebeen found in the CSF of PD patients (El-Agnaf et al., 2006). Levels
of transaminase acting on huntingtin are markedly increasedin the
CSF of HD patients (Jeitner et al., 2001). The CSF levels of these
markers reflect changes in the metabolism of these proteins in the
central nervous system. Other biomarkers, such as increased levels
of 4-HNE,are an indication of oxidative stress. These biomarkers in
the CSF can be used not only to diagnose neurodegenerative
conditions, but also to monitor the patients response to the
therapeutic drugs. This may simplify and shorten early clinicaltrials that examine the efficacy of various drugs. The diagnosis of
neurodegenerative diseases by CSF markers can be combined with
the clinical information and brain-imagingtechniques (SPECT, PET,
and MRI) for improved detection of neurodegenerative diseases.
Accurate early diagnosis is the key for effective long-term
treatment and management of neurodegenerative diseases. Early
referral of all cases suspected of having neurodegenerative
diseases for specialist assessment and advice is strongly recom-
mended.
6. Can aging be delayed?
Aging is a complex, progressive and universal process,
originating endogenously, that manifests during postmaturationallife. It is controlled not only by genes, but also by common factors
such as nutrition, exercise, attitude, mental relaxation, and
socialization (Karting, 2001). In addition, environmental factors
influence the human lifespan. Two basic molecular traits are
associated with the rate of aging and thus with the maximum life
span: the presence of low rates of mitochondrial oxygen radical
production, and low levels of fatty acid unsaturation in the cellular
membranes in postmitotic tissues of long-lived homeothermic
vertebrates compared with those of short-lived ones (Pamplona
et al., 2002). The mortalityrates of lifestyle-related diseases suchas
heart disease, stroke, neurodegenerative diseases, and cancer are
increasing in United States, where much of the baby boomer
population is becoming old (Shimizu and Shirasawa, 2008). The
preventive measures for lifestyle-related diseases, such as nutri-tional intervention or regular physical exercise, may extend the
healthy lifespan. Caloric restriction (CR) in experimental animals
has been shown to extend the lifespan of animals with a decrease
in the frequency of age-related neurodegenerative diseases.
Although aging can not be controlled, it is certainly possible to
stay healthy and to delay aging by monitoring factors such as the
selection of diet, caloric restriction, physical activity, and regular
consumption of anti-aging remedies (Shimizu and Shirasawa,
2008).
6.1. Selection of diet
In order to increase the quality of life in the aging population, it
is crucial to explore methods that may retard or reverse the
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deleterious effects of aging. Diets enriched with anti-oxidant and
anti-inflammatory agents (curcumin, green tea, and ferulic acid)
may lower the risk of developing age-related neurodegenerative
diseases such as AD and PD (Table 2). Many studies indicate that
dietary supplementation with fruit or colored vegetable extracts
can decrease the age-enhanced vulnerability to oxidative stress
and inflammation. Additional studies indicate that polyphenolic
compounds found in red wine and fruits such as blueberries mayexert their beneficial effects through signal transduction and
neuronal communication, delaying dementia (Ruitenberg et al.,
2002; Lau et al., 2007; Joseph et al., 2007). Other food-based anti-
oxidants (such as vitamins C and E, b carotene, curcumin, andgreen tea) may modulate primary as well as secondary processes
of aging by neutralizing free radicals. An imbalance between free
radical production and anti-oxidant defense leads to an oxidative
stress state, which may be involved in aging processes and even
in some pathologies. Therefore, diet enrichment with anti-
oxidants may protect brain tissue and result in successful aging
(Suter and Vetter, 1994; Cabrera et al., 2006). Another important
dietary factor is the ratio between arachidonic acid and
docosahexaenoic acid. Both these fatty acids are essential for
human health. AA and DHA cannot be synthesized de novo bymammals; they, or their precursors, must be ingested from
dietary sources and transported to the brain (Horrocks and
Farooqui, 2004; Marszalek and Lodish, 2005; Farooqui, 2009). AA
is found in vegetable oil, whereas DHA in enriched in fatty fish
and fish oil. In the present day Western diet, the ratio of AA to
DHA is about 18:1. The Paleolithic diet, on which human beings
evolved and lived for most of the species existence, has a ratio of
1:1 (Simopoulos, 2006; Cordain et al., 2005; Farooqui, 2009).
Changes in eating habits, natural versus processed food, and
agriculture development within the past 100150 years have
caused these changes in the n-6 to n-3 ratio, which has affected
human health remarkably.
The consumption of fish and fish oil has numerous beneficial
effects on the health of the human brain (Horrocks and Farooqui,2004; Farooqui, 2009). The beneficial effects of docosahexaenoic
acid on the human brain are not only due to its effect on the
physicochemical properties of neural membranes, but also to the
modulation of neurotransmission (Chalon et al., 1998; Hogyes
et al., 2003; Chalon, 2006; Joardar et al., 2006), gene expression
(Farkas et al., 2000; Barcelo-Coblijn et al., 2003; De Caterina and
Massaro, 2005; Deckelbaum et al., 2006), enzyme activities, ion
channels, receptors, and immunity (Yehuda et al., 2005; Isbilen
et al., 2006). Extra-virgin olive oil (unprocessed olive oil) contains
micronutrients and polyphenolic anti-oxidants including tyrosol
[2-(4-hydroxyphenyl)ethanol], hydroxytyrosol, oleuropein, and
oleocanthal. These compounds may not only increase longevity,
but also retard neurodegenerative diseases (Lopez-Miranda et al.,
2007).
6.2. Caloric restriction
Caloric restriction is considered to be a non-genetic interven-
tion that has consistently been shown to slow the intrinsic rate of
aging in mammals. Caloric restriction refers to the reduction in
calorie intake by maintaining essential nutrient requirements.
According to Dr. Mark Mattson, CR is the most prominent dietary
factor that affects aging and susceptibility to chronic diseases,including neurodegenerative diseases, heart disease and cancer
(Mattson, 2008). Excessive calorie intake increases the risk of age-
related chronic diseases such as AD, PD, and HD. Reducing energy
intake by controlled CR or intermittent fasting increases lifespan
and protects brain against neurodegenerative diseases in part, due
to hormesis mechanisms that increase cellular stress resistance
(Mattson, 2008).
Several interrelated cellular signaling molecules are associated
with hormesis. These include gases (like oxygen, carbon monoxide
and nitric oxide), a neurotransmitter (glutamate), the calcium ion,
and tumor necrosis factor. In each case, low levels of these
signaling molecules are beneficial and protect against neurode-
generative disease, whereas high levels can cause neurodegenera-
tion (Mattson, 2008). Cellular signaling pathways and molecularmechanisms that mediate hormetic responses involve genes and
enzymes such as kinases and deacetylases, the sirtuin-FOXO
pathway, and transcription factors such as Nrf-2 and NF-kB. As a
result, cells increase the expression of cytoprotective and
restorative proteins including growth factors, anti-oxidant
enzymes, and protein chaperones (Mattson, 2008; Son et al.,
2008). Phytochemicals that protect neural cells (Liu et al., 2008)
exhibit biphasic dose responses on cells, with low doses activating
signaling pathways that result in increased expression of genes
encoding cytoprotective proteins including anti-oxidant enzymes,
protein chaperones, growth factors and mitochondrial proteins
(Mattson, 2008; Son et al., 2008) (Fig. 5). Examples include the
activation of the nuclear factor-E2-related factor-2-Nrf2-anti-
oxidant response element (Nrf-2-ARE) pathway by sulforaphane(an anticancer and antimicrobial compound) and curcumin
(principal component of turmeric), the activation of transient
receptor potential (TRP) ion channels by allicin (major component
of garlic) and capsaicin (the active component of chili peppers),
and the activation of sirtuin-1 by resveratrol. A better under-
standing of hormesis mechanisms at the cellular and molecular
levels may lead to prevention and treatment of many chronic
neurodegenerative diseases. Thus, studies on dose response and
kinetic characteristics of the effects of dietary factors on human
brain tissue are urgently needed (Mattson, 2008; Son et al., 2008).
Studies of CR in animals indicate that it not only enhances
immune responses and stimulates DNA repair systems, but also
handles outside threats, suchas infectious agents, toxins, radiation,
extreme temperatures, and may delay the onset of chronic visceral
Table 2
Currently available anti-aging remedies for elderly population.
Anti-aging remedies Beneficial activity Reference
Curcumin Anti-oxidant and anti-inflammatory Aggarwal et al. (2007)
Blueberry (anthocyanins) Anti-oxidant, anti-angiogenic and anti-atherosclerotic Zafra-Stone et al. (2007)
Polyphenolic compounds and resveratrol Anti-oxidant, anti-athero-genic and anti-inflammatory Liu et al. (2008)
Sulfur compounds (allicin, alliin and agoene) Anti-platelet aggregatory, Anti-atherosclerotic, anti-oxidative,
anti-tumor, anti-thrombotic, anti-bacterial, anti-fungal
and anti-hypertensive
Amagase (2006)
n-3 fatty acids (DHA and EPA) Anti-oxidant and anti-inflammatory Horrocks and Farooqui (2004); Farooqui (2009);Antypa et al. (in press)
Extr a-virgin olive oil Ant i-p latelet aggregatory , anti-t um or and anti-oxidative Lopez-Miranda et al. (2007)
Ginkg o bilo ba Anti-platel et agg regatory, anti-oxidative and memo ry enhancer Bastianetto and Quirion (2002)
Ferulic acid Anti-oxidant Calabrese et al. (2004); Mamiya et al. (2008)
Dark choco late Improve s coronary va scul ar func ti on a nd dec reases platelet adhesio n Flammer et al. (2007)
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and brain diseases (Masoro, 2000; Longo and Finch, 2003).
Alterations in the characteristics of carbohydrate and oxidative
metabolism in response to CR have been observed (Masoro, 2000).
These alterations may, at least in part, underlie the anti-aging
action of CR. Several theories have recently been proposed to
explain molecular mechanisms responsible for the anti-aging
action of CR, but none has been tested by rigorously designed
studies (Hart et al., 1999).
One theory involves the altered metabolic characteristics of
glucose fuel use and of oxidative metabolism. The other relates to
the enhanced ability of food intake-restricted rodents to cope with
challenges, a process linked in turn to the glucocorticoid system
and to the heat-shock protein system (Calabrese et al., 2004).
Another promising hypothesis is based on the fact that CR protects
rats and mice of all ages against the damaging actions of acute
stressors (Orrell and ODwyer, 1995). This protective action against
stressors may play a major role in the anti-aging action of CR
(Masoro, 1996). Finally, another theory that may explain beneficial
effects of CR is regulation of cellular Ca2+-regulating system in
neural cells (Mattson, 2007).
Calcium is a universal second messenger within neural cells. It
is associated with multiplecellularfunctions,such as the release of
neurotransmitters, gene expression, proliferation, excitability, and
regulation of apoptosis. The magnitude, duration, and shape ofstimulation-evoked intracellular calcium are modulated not only
by the permeability of Ca2+ channels but also by the neuronal
calcium-buffering systems. Alterations in Ca2+-regulating system-
mediated signal transduction processes cause synaptic dysfunc-
tion, impaired plasticity and neuronal degeneration. It is becoming
increasingly evident that changes in Ca2+-regulating system-
mediated signal transduction processes at the cellular and
subcellular levels play an important role in normal aging and
age-related neuronal dysfunction in neurodegenerative diseases
(Mattson, 2007; Toescu and Verkhratsky, 2007; Thibault et al.,
2007). Thus, at the plasma membrane level, Ca2+-regulating
systems modulate the permeability of voltage-gated Ca2+ channels,
the activities of Ca2+-ATPases, and glucose and glutamate
transporters. At the endoplasmic reticulum level, changes inCa2+-regulating systems influence presenilin1 metabolism, and the
permeability of inositol trisphosphate receptors. At the mitochon-
drial level, Ca2+-regulating systems modulate electron transport
chain proteins, Bcl-2 family members, and proteins associated
with mitochondrial uncoupling (Mattson, 2007). Increased mito-
chondrial calcium uptake may represent a weak point in cellular
compensation, as this process overtime may contribute to cell
death. Adverse effects of aging on neural cell Ca2+-regulating
system-mediated signal transduction processes also include
perturbed energy metabolism, and mutations in the aggregation
of neurodegenerative disease-related proteins (amyloidb-peptide,a-synuclein, huntingtin, presenilins, Cu/Zn-superoxide dismutase,and apolipoprotein E). All these factors have been implicated in
normal aging and in the pathogenesis of neurodegenerativediseases (Mattson, 2007). Aging also disturbs the cellular redox
balance, producing higher levels of ROS and reactive nitrogen
species (RNS) that either directly damage cellular constituents or
indirectly alter cellular function through the activation of redox-
sensitive transcription factors, thus altering gene expression (Kim
et al., 2002). It has been reported that CR reduces the generation of
ROS and RNS, which suppress the activation of redox-sensitive
transcription factors, and minimizes the increase in expression of
inflammatory and oxidative stress gene clusters (Cao et al., 2001).
Furthermore, CR decreases the levels of F2-isoPs in plasma, liver,
and kidney (Ward et al., 2005).
Collectively, these studies suggest that caloric restriction not
only modulates Ca2+-dependent processes, but also reduces the
production of ROS and RNS (Barja, 2002). As stated above, CR
increases the expression of cytoprotective and restorative proteins,
including growth factors, anti-oxidant enzymes, and protein
chaperones such as heat-shock proteins. CR also reduces inflam-
matory risk factors by turning off activated transcription factors,
and thereby induces resistance to age-related chronic diseases. CR
modifies acyl composition of neural membrane bilayers, and is
associated with decreased membrane lipid peroxidation and
lifespan extension. These observations haveyielded the membrane
pacemaker hypothesis of aging (Hulbert, 2007). Collectively, these
studies suggest that CR and nutritional intervention may exert
therapeutic protection against age-related deficits and neurode-
generative diseases.
6.3. Planned exercise program
It is well known that mitochondrial dysfunction and oxidant
production, in association with an accumulation of oxidative
damage, contribute to the aging process. Regular physical exercise
can delay the onset of morbidity, increase mean lifespan, and
reduce the risk of developing neurological disorders. Exercise helps
to control weight, glucose levels, and blood pressure. It also
elevates high-density lipoprotein (HDL, good cholesterol) levels.
However, physical exercise also increases oxidative stress and
causes disruptions of the homeostasis. Planned training can havepositive or negative effects on oxidative stress depending on its
load, specificity and the basal level of training (Finaud et al., 2006).
Regular exercise helps in delaying aging and the onset of
neurodegenerative diseases (Larson et al., 2006). Collective
evidence suggests that lifelong exercise attenuates multiple
molecular markers of age-related oxidative damage in the
cerebellum. In addition, modest exercise initiated late in life can
have a beneficial effect on lipid oxidation and motor function ( Cui
et al., in press). In addition, exercise training also reduces oxidative
stress and glucocorticoid-mediated effects during aging and
neurodegenerative diseases (Kiraly and Kiraly, 2005).
7. Anti-aging medicine
Brains of neurodegenerative patients (such as in AD) undergo
many changes, such as the degradation of neural membrane
glycerophospholipids, the disruption of protein synthesis and
degradation, and the generation of ROS and RNS. Among these,
oxidative stress and nitrosative stress are major factors that affect
the aging process. In vertebrate models, maximum lifespan has
been shown to be inversely proportional to the rate of endogenous
free radical generation and the degree of unsaturation of tissue
fatty acids. Thus, by increasing the dietary intake of anti-oxidants
and DHA-enriched food, one can help the body to defend itself.
These factors can be modified through lifestyle changes, by using
pharmacological agents (such as statins, anti-hypertensive agents)
and age-related drugs (such as anti-oxidants and estrogen
replacement therapy). The expression and progression of theneurodegenerative processes of brain aging, AD, and other relative
neurodegenerative diseases can be delayed by altering the balance
between neuronal damage and repair (Ball and Birge, 2002;
Farooqui, 2009).
It is well known that a neurons life span is modulated by its
energy status (Farooqui and Horrocks, 2007). Sirtuins are a family
of NAD+-dependent enzymes that deacetylate substrates ranging
from histones to transcriptional regulators, with the subsequent
formation of nicotinamide and O-acetyl-ADP ribose. The depen-
dence of sirtuins on NADlinks sirtuin activity directly to the energy
status of the cell via the cellular NAD:NADH ratio and the absolute
levels of NAD, NADH or nicotinamide. Sirtuins have been
implicated in the regulation of the molecular mechanisms of
aging. The overexpression of sirtuin leads to lifespan prolongation
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in Saccharomyces cerevisiae and Caenorhabditis elegans that canalso
be reached with CR. Increase in SIRT1 activity (a human NAD+-
dependent protein deacetylase) decreases glucose levels, improves
insulin sensitivity, increases mitochondrial number and function,
decreases production of ROS, improves exercise tolerance, and
potentially lowers body weight (Guarente, 2007). Activation of
SIRT1 mediates the enhancement in activity of multiple proteins,
including peroxisome proliferator-activated receptor coactivator-
1a (PGC-1a) and FOXO, which help in mediating some of the invitro and in vivo effects of sirtuins. SIRT1 not only modulates gene
silencing, DNA repair, rDNA recombination, and aging, but also
regulates apoptosis (Pallas et al., 2008). Thus, an increase in SIRT1
activity protects neural cells against b-amyloid-mediated ROSproduction and DNA damage, and protects against apoptotic death
in vitro. It is also reported that neurons in AD and HD can be
rescued by the over-expression of SIRT1, induced by either CR or
administration of resveratrol, a potential activator of this enzyme.
Pretreatment with resveratrol protects neural cells against
cerebral ischemia (Ravel et al., 2008). The resveratrol-mediated
neuroprotective effect is similar to ischemic preconditioning-
induced neuroprotection against lethal ischemic insult to the
brain. The inhibition of SIRT1 blocks ischemic preconditioning-
induced neuroprotection in the CA1 region of the hippocampus
(Ravel et al., 2008).In mammalian systems, sirtuin activators are known to protect
against axonal degeneration and poly-glutamine toxicity, suggest-
ing the potential therapeutic value of sirtuins in patients with
neurodegenerative diseases, such as AD, PD, and HD. Microarray
analysis of resveratrol-treated human dermal fibroblasts indicates
that genes involved in the Ras and ubiquitin pathways, Ras
protein-specific guanine nucleotide-releasing factor 1 (Ras-GRF1),
receptor-associated coactivator 3 (RAC3), and ubiquitin-conjugat-
ing enzyme E2D 3 (UBE2D3), are downregulated. Based on a
detailed investigation of theeffect of resveratrol, it is proposedthat
resveratrol-induced changes may alter sirtuin-regulated down-
stream pathways rather than sirtuin activity (Stefani et al., 2007).
Collective evidence suggests that the activation of sirtuin extends
lifespan and promotes longevity and healthy aging in a variety ofspecies, potentially delaying the onset of age-related neurode-
generative disorders (Pallas et al., 2008; Rossi et al., 2008; Gan,
2007; Alvira et al., 2007).
Anti-aging medicine is a field of clinical endeavors aimed at
preventing and curing age-related diseases. Anti-aging compounds
stimulate and add natural human elements to help ensure that
the body is able to repair, regenerate, and protect itself (Arking
et al., 2003). The development of specific anti-aging treatments
and the emergence of the practice of anti-aging medicine have
attracted considerable attention in recent years. The most common
anti-aging medicines include nootropic piracetam, ginkgo biloba,
resveratrol, quercetin, catechin, curcumin, ferulic acid, carote-
noids, flavonoids, and estrogens (Table 2). Molecular mechanisms
associated with the neuroprotective actions of these anti-agingmedicines are not fully understood. However, these medicines not
only block oxidative and nitrosylative stress but also exert health
benefits by inducing adaptive cellular stress responses. Available
datafrom limited human clinical practice and experimental animal
studies indicate that treatments with ginkgo biloba, resveratrol,
quercetin, catechin, curcumin, ferulic acid, and flavonoids not only
improve memory and brain metabolism, but also enhance
tolerance to oxidative and nitrosative stress. Collective evidence
from studies suggests that these compounds have great potential
to combat against normal human brain aging and age-related
neurodegenerative diseases.
Dietary supplementation with fruit or vegetable extracts
decreases the age-enhanced vulnerability to oxidative stress and
inflammation. Several studies have indicated that polyphenolic
compounds found in fruits such as blueberries may exert their
beneficial effects through signal transduction and neuronal
communication. Collective evidence suggests that nutritional
supplementation with polyphenolic compounds may exert ther-
apeutic protection against age-related deficits and neurodegen-
erative diseases (Lau et al., 2007). The use of anti-aging remedies
along with physical activity stimulate the regeneration of neurons
in the old brain, and boost the performance of mental and physical
tasks. Collective evidence suggests that physicians already have
anti-aging treatments at their disposal. However, the influence
of such treatments on life span of humans has not been studied.
The increase in humanlife expectancy at birth in the second half of
the last century is mostly caused by enhanced survival at old age.
The use of neuroprotective and regenerative drugs is increasing in
the elderly population of the Western world, and it is suggested
that the use of medicines exerting anti-aging properties may
contribute to an increase in human longevity.
Anti-aging remedies (active prevention) dose not stop or
reverse the aging process. By recognizing and decreasing the risks
of developing chronic diseases provoked by genetic disposition,
lifestyle, and biochemical changes, one can elaborate preventive
strategies. Several factors may account for the slow progress of
anti-aging research. Foremost is a practical problem: the
exceptionally slow biological process of human aging. Anotherproblem is that some of these anti-aging treatments and products
are actually ineffective, and can seriously harm the consumers
(Mehlman et al., 2004). Thus, current anti-aging therapies are
associated with a number of concerns regarding their safety and
efficacy, and the prescription of these therapies is becoming a
challenge from both a legal and ethical perspective (de Grey, 2003;
Grossman, 2005).
8. Conclusion
Aging is an important factor for the pathogenesis of neurode-
generative diseases. Many theories of aging have been proposed
over the years, and no single theory accounts for all the changesthat occur in aging. Aging is a multi-factorial, complex and
inexorable process. An increasedsusceptibility and vulnerability to
diseases at old age in humans may be due to a decline in
physiological functions and a decrease in the ability to cope with
oxidative stress. The field of aging research has exploded with new
information. Researchers have demonstrated the role of several
genes, including vitagenes and sirtuin genes that may modulate
aging and influence longevity. The goal of researchers should be to
not only evaluate how to enhance human longevity, but also to
determine how to remain active and disease-free during aging
(healthy longevity).
Neurodegenerative diseases are multi-factorial diseases that
have complex mechanisms due to multiple pathogenic events. An
unbalanced overproduction of ROS and RNS may give rise to
oxidative and nitrosylative stresses, which can induce neuronal
damage resultingin neuronal death by apoptosis or necrosis. These
diseases are a result multiple genetic defects, and they depend on
the mutations as well as susceptibility to epigenetic or environ-
mental factors. Understanding the pharmacogenomics of neuro-
degenerative diseases may prove beneficial, as it will accelerate the
development of new anti-aging drugs with higher efficacy and
fewer side effects.
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